Consumption of ethanol (EtOH) to produce blood levels greater than 0.15% causes a neuroendocrine stress response in humans and in rodent models. Similar stress responses to other stimuli are associated with decreased natural killer (NK) cell activity. A single dose of EtOH produces a substantial stress response in B6C3F1 mice and basal NK cell activity is suppressed, at least in part, by glucocorticoids and catecholamines produced as a consequence of this stress response. Activation of NK cells by Type 1 interferon-inducer polyinosinic polycytidylic acid (poly I:C) is inhibited by EtOH. Therefore, the present project will evaluate the mechanism by which EtOH suppresses activation of NK cells (in a mouse model), and the project will evaluate the role of key neuroendocrine mediators in this suppression. The following hypothesis will be tested: The mechanism by which acute EtOH administration inhibits activation of NK cells involves glucocorticoids and catecholamines. These mediators act by altering survival, trafficking or activation of NK cells. The following specific aims will be used to test the hypothesis: 1) Determine the role of EtOH-induced neuroendocrine mediators in preventing NK cell activation, and determine if the effects of EtOH on NK cells are mediated by another cell type, 2) Evaluate the mechanism by which EtOH and EtOH-induced neuroendocrine mediators prevent induction of increased splenic NK cell activity by determining the effects of EtOH on NK cell survival, trafficking and several aspects of cell activation, and 3) Determine the effects of EtOH (and neuroendocrine mediators) in a host resistance model in which NK cell activation is known to be important. This provides a comprehensive approach in which all of the major components or processes known to be important in NK cell activation and movement to a site of cancer or infection will be evaluated to experimental metastases of B16F10 melanoma in the lungs. The role of glucocorticoids and catecholamines in these effects will be determined, because mediators are involved in inhibition of poly I:C-enhanced NK cell activity. These results have implications for human health, because even moderate EtOH consumption increased the incidence of cancer and many persons with EtOH-associated cancers have decreased NK cell function.